May 3, 1999
Volume 51, No. 30
New vaccine provides protection from HIV in monkeys
AIDS researchers at the Yerkes Center have created a DNA vaccine that protects monkeys against a formidable challenge HIV virus. Achieving protection with this vaccine, made with harmless components from a SHIV--a blend of parts from HIV and SIV (simian or monkey immunodeficiency virus)--marks a significant and promising step toward the development of an effective AIDS vaccine. The study results are reported in the May issue of Nature Medicine by Harriet Robinson, chief of microbiology and immunology at Yerkes.
In a three-year study, Robinson compared combinations of three different vaccine approaches and two different delivery methods. The most effective vaccination involved two steps. The first consisted of "priming" the immune system with a DNA vaccine consisting of genes taken from SHIV. The genes express specific SHIV proteins that help the body produce an initial immune response. This was followed, at 46 and 66 weeks, with "booster" immunizations with the same SHIV DNA inserted into a pox virus. The pox virus deftly invades the host's cells, expressing very high levels of useful SHIV proteins. However, once in the cells, the virus itself does not replicate, and thus poses no risk of unwanted dissemination in the vaccinated individual.
Robinson also tested two different ways of introducing the DNA vaccine. Inoculation through the skin (intradermal) proved more effective in containing viral challenges than did administration with a "gene gun," which bombards cells with DNA-coated gold beads.
The vaccine was successful in containing the virus over a 62-week period, during which a series of three SHIV challenge infections were administered. The containment was remarkably effective, preventing detectable levels of virus in blood at all times post-challenge-in contrast to unvaccinated animals, which had viral loads of up to 1 billion. "This holds promise for the development of a vaccine capable of seriously reducing viral replication and stemming the transmission of AIDS," said Robinson.
Most scientists believe an AIDS vaccine will be completely effective only if it involves both components of the immune response: humoral and cellular immunity. Humoral immunity refers to the process in which B lymphocytes (a type of white cell) secrete antibodies that recognize and fight off viruses and other invading microbes. This occurs while the intruders are still in the blood and lymph systems, before they can invade individual cells in the body. The second line of defense is cellular immunity, where T lymphocytes recognize when host cells have become infected and destroy them. T cells do not secrete antibodies; they must come near or actually make contact with the infected cell to destroy it.
Development of an AIDS vaccine has proven particularly challenging because the HIV virus is able to elude the antibody response as well as destroy the helper T cells that are central to raising a cellular immune response. In addition, HIV is capable of establishing a latent reservoir of viral DNA that the immune system fails to recognize, and that later re-emerges to cause disease even if the initial infection has been contained.
Among the AIDS vaccines that previously have been tested in macaque models, only live attenuated viruses, with their potential risks for actually causing disease, were able to protect the animals against highly pathogenic challenges. Three safer approaches for vaccination have held promise, but only against less virulent strains of HIV. They are safer because they use non-pathogenic pieces of virus to stimulate immune response instead of the entire virus. For this reason they are called "sub-unit" viruses.
Robinson decided to test different combinations of three sub-unit approaches. "It was important to test whether vaccines that were providing some success when used individually could have synergy and elicit a stronger response when used together," she said.
The sub-unit methods include:
In testing combinations of these three approaches, Robinson's results show the animals able to combat SHIV challenge infections were the ones who received the first two methods-- intradermal DNA vaccine "primes" plus recombinant pox virus "booster" shots. The containment of the virus was apparently cell-mediated, as neutralizing antibodies were undetectable.
Future studies for Robinson's group include expanded testing in preclinical models of the protective qualities of her two-step protocol and extending trials into Phase I studies in humans.